Adenosine as a Marker and Mediator of Cardiovascular Homeostasis: A Translational Perspective

Abstract

Adenosine, a purine nucleoside, is produced broadly and implicated in the homeostasis of many cells and tissues. It signals predominantly via 4 purinergic adenosine receptors (ADORs) – ADORA1, ADORA2A, ADORA2B and ADORA3 in addition to non-ADOR mediated effects. Through these signaling mechanisms, adenosine exerts effects on numerous cell types crucial to maintaining vascular homeostasis, especially following vascular injury. Both in vitro and in vivo models have provided considerable insights into adenosine signaling and identified targets for therapeutic intervention. Numerous pharmacologic agents have been developed that modulate adenosine signaling, both through design as specific ADOR agonists and antagonists and as offtarget effects of existing anti-platelet medications. Despite this, adenosine has yet to be firmly established as either a therapeutic or a prognostic tool in clinical medicine to date. Herein, we provide a bench-to-bedside review of adenosine biology, highlighting the key considerations for further translational development of this promising molecule.

Performance of Plasma Adenosine as a Biomarker for Predicting Cardiovascular Risk

“…Whereas circulating adenosine levels may not predict future events, this does not exclude adenosine as a viable therapeutic target, particularly when considering its tissue‐level characteristics. As discussed, numerous agents known to modulate adenosine have shown favorable impacts on vascular healing and cardiovascular outcomes, including dipyridamole, 1 cilostazol, 7,8 and ticagrelor 9 . Although all of these agents have demonstrated favorable impact on clinical outcomes, the mechanism of action may be on local rather than circulating adenosine levels.…”

“…Adenosine serves as a crucial regulatory molecule in both intracellular and extracellular processes 1 . Adenosine homeostasis is closely regulated by an ongoing balance of production, degradation, and transport 2,3 .…”

“…These receptors are found on a multitude of vascular cells with differing responses based upon the cell and receptor subtypes. Accordingly, adenosine signaling has been implicated in vascular homeostasis with considerable preclinical data supporting its role in vasculoprotection 1 …”

“…Indeed, adjunctive agents that augment adenosine levels have demonstrated promising results. Dipyridamole, augmenting adenosine through equilibrative nucleoside transporter‐1 (ENT‐1) inhibition, has demonstrated improved vascular patency and reduced restenosis in preclinical and clinical studies 1 . Similarly, cilostazol modestly augments adenosine levels in addition to cyclic adenosine monophosphate, 7 yielding reduced restenosis following coronary stenting 8 .…”

<p>ATAS Acupuncture Reduces Chemotherapy Induced Fatigue in Breast Cancer Through Regulating ADROA1 Expression: A Randomized Sham-Controlled Pilot Trial</p>

“…ADORA1 is involved in down regulating inflammatory factors and promoting smooth muscle cell proliferation. 26 After long-term caffeine treatment, combined with caffeine and gossypol or agomelatonin, ADORA1 was involved in an antidepressant like effect, 27 and caffeine withdrawal resulted in a decrease in the level of ADORA1 mRNA in the cerebral cortex. 28 Through the mechanism of no/cGMP/PKG/ KATP intracellular signaling pathway, peripheral activation of ADORA1 reduces inflammatory pain sensation.…”